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The Sweet Spot in Treatment of Heart Failure With Reduced Ejection Fraction: SGLT2 Inhibitors

Sasha Prisco, MD, PhD

I am pleased to have the opportunity to summarize an important recent paper on the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors by Drs. Muthiah Vaduganathan, Gregg Fonarow, and colleagues in JAMA Cardiology,1 that was published simultaneously with AHA20.

Background:

SGLT2 inhibitors are a class of medications that were initially developed for management of diabetes but were serendipitously found to be effective in treating individuals with heart failure. In May 2020, dapagliflozin became the first SGLT2 inhibitor approved by the US Food and Drug Administration (FDA) for use in patients with heart failure with reduced ejection fraction (HFrEF) after the pivotal Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, which showed that dapagliflozin reduced heart failure events and mortality.2 In the EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial, use of another SGLT2 inhibitor, empagliflozin, was also found to reduce risk of cardiovascular death and heart failure hospitalizations.3

Major Question Addressed in the Paper: What proportion of contemporary patients with HFrEF in the US are potentially eligible for initiation of dapagliflozin based on the FDA label?

Approach: The investigators studied patients with HFrEF (EF≤40%) who were in the AHA Get With The Guidelines-Heart Failure (GWTG-HF) registry. They assessed patients admitted between January 2014 to September 2019 at 529 sites (started with 586,580 patients). Patients were excluded if they had any of the following based on the FDA label for dapagliflozin: estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m2 at discharge, dialysis (either history of chronic dialysis or required dialysis during hospitalization), and/or type 1 diabetes. After excluding patients who met the aforementioned criteria and those who had missing discharge eGFR or vital signs, the primary study cohort consisted of 154,714 patients at 406 sites.

Major Results:

  • Of the 154,714 patients studied in the GWTG-HF registry, 125,497 (81.1%) were candidates for initiation of dapagliflozin based on the FDA label.
  • When only looking at sites with ≥10 hospitalizations (355 sites that enrolled 154,522 patients), the median proportion of dapagliflozin candidates was still 81.1% (25th-75th percentiles 77.8-84.6%).
  • A higher proportion of patients without type 2 diabetes than with type 2 diabetes were candidates for dapagliflozin (85.5% vs. 75.6%).
  • The most frequent reason for not meeting the FDA label was eGFR<30 mL/min/1.73 m2, which was met more frequently in patients with a history of or new diagnosis of diabetes than those without diabetes (23.9% vs. 14.3%).
  • There was lower use of evidence-based heart failure therapies in the GWTG-HF patients compared to patients in the DAPA-HF trial.

Histogram from Vaduganathan et al. evaluating the proportion of patients meeting the dapagliflozin FDA label criteria from hospitals with at least 10 eligible HFrEF hospitalizations.

Major Study Limitations: Since the GWTG-HF data are de-identified, only unique hospitalization episodes were presented so some patients may be represented more than once in this study. Glycated hemoglobin levels were not measured in a protocolized way, thus type 2 diabetes could be underdiagnosed in this study. Data regarding post-discharge labs and the use of therapies were not available.

Key Take Home Message: This study using a large AHA registry (GWTG-HF) strikingly found that 4 out of 5 adults with HFrEF (regardless of whether the patient has type 2 diabetes) may be eligible for initiation of dapagliflozin, supporting the broad applicability of this therapy in US clinical practice.

For further learning, there are several great OnDemand sessions from AHA20 on SGLT2 inhibitors.

AHA20 OnDemand Sessions on SGLT-2 inhibitors:

  • New Glucose-Lowering Agents with CV Benefits: Working… But How?
  • SGLT2i for Non-Diabetic Indications: Updates from Mega-Trials and Mechanistic Insights
  • Novel Anti-Diabetic Agents: A Tidal Wave of Change in the Cardiovascular Care of Patients with CKD
  • The Heart, the Kidney, and SGLT2 Inhibition: For Clinical Trials to Patient Care

Potential Future Research Directions:

  • Determine the mechanisms leading to the efficacy of SGLT2 inhibitors in HFrEF.
  • Investigate the renal effects of SGLT2 inhibitors and whether SGLT2 inhibitors can be safely used in patients with more severe chronic kidney disease.
    • DAPA-CKD4 (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), which included patients with eGFR as low as 25 mL/min/1.73 m2, showed that dapagliflozin reduced risk of sustained eGFR decline of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes regardless of the presence or absence of type 2 diabetes.
    • EMPEROR-Reduced included HFrEF patients with eGFR as low as 20 mL/min/1.73 m2.
  • Evaluate whether SGLT2 inhibitors are beneficial in patients with heart failure with preserved ejection fraction (HFpEF). Current ongoing/future clinical trials with HFpEF patients include DELIVER (NCT03619213), EMPEROR-Preserved (NCT03057951), EMPA-HEART 2 (NCT04461041), PRESERVED-HF (NCT03030235), and EMBRACE-HF (NCT03030222).
  • Assess the effects of simultaneous use of SGLT2 inhibitors and another class of diabetic medications that have shown beneficial cardiovascular disease (CVD) effects, glucagon-like peptide-1 receptor agonists (GLP-1RA) and determine which of these two classes of medications should be prioritized in drug-naïve patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD).

Potential mechanisms underlying the beneficial effects of SGLT2 inhibitors. Figure from Dr. Subodh Verma’s talk entitled “SGLT2 inhibitors: Why do they work” in the “New Glucose-Lowering Agents with CV Benefits: Working… But How?” session at AHA20.

 

References

  1. Vaduganathan M, Greene SJ, Zhang S, Grau-Sepulveda M, DeVore AD, Butler J, Heidenreich PA, Huang JC, Kittleson MM, Joynt Maddox KE, McDermott JJ, Owens AT, Peterson PN, Solomon SD, Vardeny O, Yancy CW, Fonarow GC. Applicability of us food and drug administration labeling for dapagliflozin to patients with heart failure with reduced ejection fraction in us clinical practice: The get with the guidelines-heart failure (gwtg-hf) registry. JAMA Cardiol. 2020
  2. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM, Investigators D-HTCa. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008
  3. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F, Investigators E-RT. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-1424
  4. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC, Investigators D-CTCa. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436-1446

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”
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Another (Louder) Call to Improve the Care We Provide Heart Failure Patients

Nasrien E. Ibrahim, MD

I am always taken aback when I recommend a switch to sacubitril/valsartan in a patient with heart failure with reduced ejection fraction (HFrEF) and the response is “my patient feels fine”. This is a common response and certainly not a good enough reason to not optimize guideline directed medical therapy (GDMT) in patients with HFrEF. Optimization of GDMT in HFrEF, known to improve morbidity and mortality (1,2), is dismal. The Change the Management of Patients with Heart Failure (CHAMP-HF) registry included patients in the United States with chronic HFrEF receiving at least one oral medication for management of HF and showed >25% of eligible patients are not prescribed angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor, >33% are not prescribed a beta blocker, >50% are not prescribed a mineralocorticoid receptor antagonist. Remarkably, even among those receiving GDMT fewer than 25% are prescribed target doses and only 1% of eligible patients are simultaneously on target doses of all 3 classes of GDMT (3,4).

The mechanisms for suboptimal prescription of GDMT in HFrEF are complex and undertreatment is even more evident among women, minority patient populations, and patients from economically disadvantaged backgrounds, among others. Cost is certainly an issue, especially with more novel HF therapies and co-pay assistance programs are not always available to our most vulnerable patients. There are not enough HF cardiologists to take care of the continuously increasing population of HF patients and therefore, optimization of GDMT needs to be done by general cardiologists and primary care clinicians as well. We should also become creative and use telemedicine to optimize GDMT more efficiently. We do our patients a disservice by not optimizing GDMT that improves HF morbidity and mortality.

And just as optimization of GDMT is not ideal, neither is our evaluation of etiology of HF. Optimization of GDMT and determination of etiology of HF whose management may change disease trajectory should be undertaken in all patients with new-onset HF. This begins with a fundamental understanding of the various etiologies of HF, the laboratory and imaging testing needed, and the best treatment strategy for the underlying etiology discovered- if any (cue, “idiopathic” cardiomyopathy). O’Connor and colleagues’ observational cohort study from the Get With The Guidelines- Heart Failure (GWTG-HF) registry demonstrates the need to improve the testing we perform to exclude coronary artery disease (CAD) as the underlying etiology of new-onset HF.4

Why is this important? Well, of course for treatment, which involves deciding whether medical therapy (aspirin, statins) or revascularization (surgical or percutaneous) is a more optimal strategy. And most important to improve disease trajectory as continued ischemia will lead to worsening HF. O’Connor and colleagues found that the majority of  17,185 patients hospitalized for new-onset HF did not receive testing for CAD either during the hospitalization or in the 90 days before and after, despite data demonstrating that 60% (!!!) of HF patients have concomitant significant CAD.4 And consistent with disparities I mentioned earlier regarding the undertreatment of women with GDMT, men were more likely to be tested for CAD.

Diagnosing and treating CAD provides an opportunity to discuss risk factor modification with patients such as smoking cessation, diabetes control, exercise, healthy diets etc.… to further mitigate future risk. The importance of optimization of GDMT in patients with HFrEF cannot be understated and analogous to this, is the importance of examining the underlying etiology of HF in patients with new-onset HF with preserved, borderline, or reduced EF to improve disease trajectory. Furthermore, inequities in both aspects of the care of HF patients in terms of identification of etiology and optimization of GDMT, must be addressed on a national level. We have plenty of data illustrating suboptimal optimization of GDMT in those with established HFrEF and suboptimal testing for CAD in those with new-onset HF. The next steps are understanding the mechanisms and implementing strategies to improve care. The need for this is critical to reduce morbidity and mortality in all HF patients.

References

  1. Yancy CW, Jessup M, Bozkurt B et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;137.
  2. Yancy CW, Januzzi JL, Allen LA et al. 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. Journal of the American College of Cardiology 2017.
  3. Greene SJ, Butler J, Albert NM et al. Contemporary Utilization and Dosing of Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction: From the CHAMP-HF Registry. Journal of the American College of Cardiology 2018.
  4. O’Connor, Kyle D., et al. “Testing for Coronary Artery Disease in Older Patients With New-Onset Heart Failure.” Circulation: Heart Failure, vol. 13, no. 4, 2020, doi:10.1161/circheartfailure.120.006963.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”
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Why Should We Care About Sex Differences in Do Not Attempt Resuscitation Orders After In-Hospital Cardiac Arrest?

Sasha Prisco, MD, PhD

As an AHA Early Career Blogger and member of the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation (3CPR), I am pleased to have the opportunity to summarize the recently published paper in the Journal of the American Heart Association (JAHA), “Do Sex Differences Exist in the Establishment of ‘Do Not Attempt Resuscitation’ Orders and Survival in Patients Successfully Resuscitated From In-Hospital Cardiac Arrest?”1 This paper was published in February during American Heart Month in the JAHA Spotlight: Go Red for Women 2020 series in conjunction with AHA’s Go Red for Women initiative.

In summary, Perman et al.1 used the Get With The Guidelines®-Resuscitation registry to determine whether there are sex differences in the establishment of “do not attempt resuscitation” (DNAR) orders after resuscitation from in-hospital cardiac arrest and whether the differences in DNAR use lead to differences in survival. They examined 71820 patients across 571 hospitals who had return of spontaneous circulation (ROSC) after in-hospital cardiac arrest and examined the association between de novo DNAR orders (any time after ROSC, within 12 hours of ROSC, or within 72 hours of ROSC) and sex and the association between sex, DNAR orders, and survival. The 72-hour time point was selected since after this time is when patients who are comatose after cardiac arrest begin to have neurologic findings that indicate poor prognosis and AHA guidelines recommend that the determination of neurologic prognosis should be delayed until at least 72 hours after ROSC (or 72 hours after reaching normothermia if targeted temperature management is used).

Of the 71820 patients, 42.4% of the cohort were women and women were on average older (mean±SD: 65.5±15.8 vs. 64.6±15.1 years; P<0.0001), less frequently of non-Hispanic white race (61.7% vs. 67.5%, P<0.0001), more likely to have a non-shockable cardiac arrest rhythm such as pulseless electrical activity (PEA) or asystole (81.6% vs. 78.0%, P<0.0001), and more likely to have a noncardiac illness at the time of admission (47.2% vs. 41.1%, P<0.0001) while men had a higher incidence of cardiac premorbid conditions.

Of the total cohort, 44.1% had a de novo DNAR order placed after ROSC. Of the entire cohort, 45.0% of women and 43.5% of men had a DNAR order after ROSC (unadjusted RR: 1.16; 95% CI, 1.12-1.21; adjusted RR [ARR]: 1.15; 95% CI, 1.10-1.20). Women had a higher rate of DNAR status early after resuscitation. Of those who had any DNAR order during the hospitalization, 51.8% of women compared to 46.5% of men had a DNAR order placed <12 hours after ROSC and 75.9% of women compared to 70.9% of men had a DNAR order placed <72 hours after ROSC. When adjusting for the patients’ demographics and cardiac arrest characteristics, female sex was associated with a higher likelihood of early DNAR <12 hours after ROSC (ARR: 1.40; 95% CI, 1.30-1.52) and DNAR <72 hours after ROSC (ARR: 1.35; 95% CI, 1.26-1.45) among those who had a DNAR order any time after ROSC.

Interestingly, after adjusting for patient and arrest characteristics, female sex was mildly associated with lower rates of survival to hospital discharge (ARR: 0.98; 95% CI, 0.96-1.00; P=0.04) and there were no differences in survival rate between men and women after adjusting for DNAR status within 72 hours. However, early DNAR status made within 72 hours of ROSC (combining data from men and women) was associated with decreased survival rate compared to those without a DNAR order or a DNAR order placed ≥72 hours after arrest (RR: 0.15; 95% CI, 0.14-0.17; P<0.0001).

This study by Perman et al.1 is not the first study to note differences in rates of do not resuscitate (DNR)/DNAR orders between men and women. Nakagawa et al.2 showed that women with acute intracranial hemorrhage were more likely to receive early (<24 hours from presentation) DNR orders than men. In a study of patients who received emergency surgery, women were more likely to receive a DNR order but morbidity and mortality rates were similar between men and women3.

Unfortunately, the reasons for women to more likely receive earlier DNR/DNAR orders are unknown at this time. Perhaps these differences could be due to patient preferences (e.g. women having earlier end of life discussions with family/surrogate decision-makers), implicit provider biases (e.g. female cancer patients were found to be more likely to receive early DNR orders from female physicians4), surrogate decision-maker biases, sociocultural factors, religious factors, situational influences, etc. Although DNR/DNAR orders are not requests for withdrawal of life-sustaining therapy, the presence of DNR/DNAR orders has previously been associated with decreased aggressive interventions and decreased survival to discharge for patients with out-of-hospital cardiac arrest5. This suggests that health care providers should be vigilant of the tendency to be less aggressive with care for patients with DNR/DNAR orders and ensure that their management plans align with the expectations of surrogate decision-makers. More robust qualitative data are needed in order to understand these differences.

References:

  1. Perman SM, Beaty BL, Daugherty SL, Havranek EP, Haukoos JS, Juarez-Colunga E, Bradley SM, Fendler TJ, Chan PS, † AHAGWTGRI. Do sex differences exist in the establishment of “Do not attempt resuscitation” Orders and survival in patients successfully resuscitated from in-hospital cardiac arrest? J Am Heart Assoc. 2020;9:e014200
  2. Nakagawa K, Vento MA, Seto TB, Koenig MA, Asai SM, Chang CW, Hemphill JC. Sex differences in the use of early do-not-resuscitate orders after intracerebral hemorrhage. Stroke. 2013;44:3229-3231
  3. Eachempati SR, Hydo L, Shou J, Barie PS. Sex differences in creation of do-not-resuscitate orders for critically ill elderly patients following emergency surgery. J Trauma. 2006;60:193-197; discussion 197-198
  4. Crosby MA, Cheng L, DeJesus AY, Travis EL, Rodriguez MA. Provider and patient gender influence on timing of do-not-resuscitate orders in hospitalized patients with cancer. J Palliat Med. 2016;19:728-733
  5. Richardson DK, Zive D, Daya M, Newgard CD. The impact of early do not resuscitate (dnr) orders on patient care and outcomes following resuscitation from out of hospital cardiac arrest. Resuscitation. 2013;84:483-487

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”